EP0955314A2 - Peptidanaloge des Glucagon-like-Peptide-1 (7-37), deren Herstellung und pharmazeutische Zusammensetzungen - Google Patents

Peptidanaloge des Glucagon-like-Peptide-1 (7-37), deren Herstellung und pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0955314A2
EP0955314A2 EP99400613A EP99400613A EP0955314A2 EP 0955314 A2 EP0955314 A2 EP 0955314A2 EP 99400613 A EP99400613 A EP 99400613A EP 99400613 A EP99400613 A EP 99400613A EP 0955314 A2 EP0955314 A2 EP 0955314A2
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EP
European Patent Office
Prior art keywords
optionally substituted
group
formula
residue
amino acid
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EP99400613A
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English (en)
French (fr)
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EP0955314B1 (de
EP0955314A3 (de
Inventor
Bernard Calas
Gérard Grassy
Alain Chavanieu
Cyril Sarrauste De Menthiere
Pierre Renard
Bruno Pfeiffer
Dominique. Manechez
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Laboratoires Servier SAS
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ADIR SARL
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new peptide compounds analogous to Glucagon-Like-Peptide-1 (7-37), their preparation process and the pharmaceutical compositions containing them.
  • Glucagon-Like-Peptides-1 (7-37) and (7-36) NH 2 are peptides of intestinal origin, strongly involved in the control of carbohydrate homeostasis. These peptides are the main mediators of the entero-insular axis and act by binding to specific receptors.
  • T GLP-1 acts predominantly at the pancreatic level by exerting a powerful effect of stimulation of insulin secretion by ⁇ cells, in a glucose dependent manner (S. Mojsov et al., J. Clin. Invest., 1987 , 79 , 619; and JJ Holst, FEBS Letters, 1987, 211 , 169). This stimulation is accompanied by a stimulation of the release of somatostatin and an inhibition of the release of glucagon.
  • t GLP-1 has the effect of slowing gastric emptying, decreasing acid secretions and stimulating the peripheral use of glucose at the muscular, hepatic and adipocytic level (ML Villanueva et al., Diabetologia , 1994, 37 , 1163; DJ Drucker, Diabetes, 1998, 47, 159).
  • T GLP-1 therefore has multiple potential therapeutic applications, in particular in the treatment of non-insulin-dependent type II diabetes, obesity, and in type I diabetes.
  • the compounds of the present invention have an original structure derived from that of t GLP-1 by modifications of several residues and / or by deletion of arginine at position 36. Besides the fact that they are new, these compounds have properties interesting pharmacological results, due to their agonist nature for t GLP-1 receptors. The modifications made have the additional advantage of considerably increasing the metabolic stability of the compounds of the invention and thus confer on them a longer duration of action than the natural peptide. These properties make these derivatives particularly interesting for the treatment of pathologies for which t GLP-1 intervenes, in particular in the treatment of non-insulin-dependent type II diabetes, obesity, and in type I diabetes.
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric acids, etc. .
  • the present invention relates in particular to the peptide compounds of formula (I), for which the residues X 1 to X 14 are chosen as a function of the nature of their side chain.
  • the latter can have an aromatic character, or an aliphatic character, or else be able to establish interactions of the hydrogen bond type, or else be able to establish ionic interactions, or else be of a cyclic nature.
  • Z 1 represents a hydrogen atom.
  • Z 2 preferably represents a group chosen from hydroxy, linear or branched (C 1 -C 6 ) alkoxy, and amino. More specifically Z 2 represents an amino group.
  • X 15 represents a bond.
  • X 2 represents an alanine residue (Ala) of configuration D or L while X 15 represents a bond.
  • X 15 represents a bond.
  • the following peptides may be mentioned more particularly:
  • the invention also extends to the process for the preparation of the compounds of formula (I) which can be obtained by various methods such as sequential synthesis on solid phase, synthesis and coupling of fragments in solution, enzymatic synthesis, or by using molecular biology techniques.
  • the solid phase synthesis is carried out on an automaton which repetitively and programmablely performs deprotection, coupling and washing cycles necessary for the sequential introduction of amino acids into the peptide chain.
  • the C-terminal amino acid is fixed on a resin conventionally used for the preparation of polypeptides, preferably a polystyrene crosslinked using 0.5 to 3.0% of divinylbenzene and provided with activated residues which allow covalent fixing of the first amino acid on the resin.
  • a resin conventionally used for the preparation of polypeptides preferably a polystyrene crosslinked using 0.5 to 3.0% of divinylbenzene and provided with activated residues which allow covalent fixing of the first amino acid on the resin.
  • the appropriate choice of resin allows the formation, after synthesis, of a C-terminal carboxylic acid, amide, alcohol or ester function.
  • the amino acids are then introduced one by one in the order determined by the operator.
  • Each synthesis cycle corresponding to the introduction of an amino acid comprises an N-terminal deprotection of the peptide chain, successive washes intended to remove the reagents or to swell the resin, a coupling with activation of the amino acid and new washes.
  • Each of these operations is followed by filtration carried out thanks to the presence of a sintered glass incorporated into the reactor in which the synthesis takes place.
  • the coupling reagents used are conventional reagents for peptide synthesis such as dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) or benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) or diphenylphosphoryazide .
  • DCC dicyclohexylcarbodiimide
  • HOBT hydroxybenzotriazole
  • BOP benzotriazol-1-yl-oxytris (dimethylamino) phosphonium hexafluorophosphate
  • BOP diphenylphosphoryazide
  • Each amino acid is introduced into the reactor 6 times in excess approximately, relative to the degree of substitution of the resin and in approximately equivalent quantity relative to the coupling agents.
  • the coupling reaction can be checked at each stage of the synthesis by the ninhydrin reaction test described by E. KAISER et al. (Anal. Biochem., 34, 595, 1970).
  • an appropriate treatment for example using a strong acid such as trifluoroacetic acid, or hydrofluoric acid in the presence of anisole, ethanedithiol or 2- methylindole is used to separate the peptide from the resin and to release the peptide from its protective groups.
  • the compound is then purified by conventional purification techniques. especially chromatographic.
  • the peptides of the present invention can also be obtained by coupling in solution of selectively protected peptide fragments, which can be prepared themselves either on solid phase or in solution.
  • the use of protective groups and the use of their differential stability is analogous to the solid phase methods with the exception of the attachment of the peptide chain to the resin.
  • the C-terminal carboxylic group is protected, for example, by a methyl ester or an amide function.
  • the activation methods during coupling are also analogous to those used in solid phase synthesis.
  • the peptides of the present invention can also be obtained using molecular biology techniques, using nucleic acid sequences encoding these peptides. These sequences can be RNA or DNA and be associated with control sequences and / or inserted into vectors. These are then transfected into host cells, for example bacteria. The preparation of these vectors as well as their production or expression in a host are carried out by conventional techniques of molecular biology and genetic engineering.
  • the synthesis of peptides containing pseudopeptide bonds is carried out either by the methods in solution or in combination with the synthesis on solid phase using the conventional methods of organic chemistry.
  • the -CH 2 -NH bond is introduced by preparing the aldehyde Fmoc-NH-CHR-CHO in solution according to the technique described by FEHRENTZ and CASTRO (Synthesis, 676-678, 1983) and by condensing it with the growing peptide chain either on solid phase according to the technique described by SASAKI and COY (Peptides, 8, 119-121, 1988), or in solution.
  • the present invention also relates to pharmaceutical compositions containing as active principle at least one compound of general formula (I) or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic excipients or vehicles.
  • compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral, nasal administration, simple or coated tablets, sublingual tablets, sachets, packages, capsules, suppositories, creams , ointments, dermal gels, transdermal patches, aerosols. drinkable and injectable ampoules ...
  • the dosage varies depending on the age and weight of the patient, the nature and severity of the condition and the route of administration.
  • This can be oral (including the inhaled, gingival and sublingual route), nasal, rectal. parenteral or transdermal. Generally, it ranges from 10 ⁇ g to 500 mg for treatment in one or more doses per 24 hours depending on the route of administration and the dosage form used.
  • Example 1 The compound of Example 1 is synthesized on a 0.1 mmole scale from an Fmoc-PAL - PEG - PS resin, using a continuous flow apparatus, following the following repetitive protocol: Operation number Function Solvent / Reagent Time 1 washing DMF 5 minutes 2 protection 20% piperidine / DMF 15 mins 3 washing DMF 15 mins 4 coupling Amino acid / DIPCDI / HOBt 60 mins 5 washing 20% piperidine / DMF 5 minutes 6 washing DMF 5 minutes 7 washing dichloromethane 5 minutes
  • Each operation, carried out at room temperature, is followed by filtration through a sintered glass incorporated into the glass cell (reactor) in which the synthesis progresses.
  • the filter retains the resin on which the growing peptide chain is attached.
  • Each amino acid (6 equivalents) is assembled using diisopropylcarbodiimide (DIPCDI) in the presence of hydroxy-1-benzotriazole (HOBt) as a coupling agent.
  • DIPCDI diisopropylcarbodiimide
  • HOBt hydroxy-1-benzotriazole
  • a peptide is obtained, protected on its side chains and fixed on the resin.
  • the support is then dried under high vacuum for 3 hours. It is then treated with 50 ml of reagent K (trifluoroacetic acid 82.5%, phenol 5%, water 5%, thioanisole 5%, ethanedithiol 2.5%). The mixture is then left at room temperature with occasional stirring for 12 hours, then filtered through an Erlenmeyer flask containing about 200 ml of ethyl ether. The peptide precipitates, and is isolated by filtration or centrifugation.
  • Example 45 Using the method described in Example 1, replacing the Fmoc-PAL-PEG-PS resin with a Moc-Gly-PAL-PEG-PS resin, the compounds of Examples 45 to 49 are obtained.
  • GLP-1 receptor binding studies were performed using TIN RIN membranes in 60 mM Tris-HCl pH 7.5 buffer, containing 4% BSA and 750 ⁇ g / ml bacitracin.
  • the membranes (20 to 30 ⁇ g) are incubated in a final volume of 500 ⁇ l with about 15 fmol of [125I] -GLP-1 (50,000 cpm) and the competitor is cold for 45 min at 37 ° C.
  • the reaction is stopped by adding 750 ⁇ l of cold KRP buffer, pH 7.5 containing 3% BSA.
  • the medium is centrifuged at 12,000 ⁇ g (4 ° C, 5 min).
  • the pellet is resuspended in 1 ml of cold KRP buffer, sedimented by another centrifugation and the radioactivity is measured. The results are expressed in IC 50 .
  • the agonist character of the compounds of the invention was determined by measuring the production of cyclic AMP after activation of the receptor by the various products to be tested.
  • TIN RIN cells are cultured for 6 days and the culture medium is changed 1 day before the experiment.
  • the cells (3.10 5 per well) are washed twice with DMEM before addition of 0.5 ml of DMEM containing 1% of BSA, 0.2 ml of IBMX and the peptide to be tested. After 20 minutes of incubation at 25 ° C, the intracellular cAMP is extracted, succinylated and quantified by radioimmunoassay.
  • the reference value at 100% corresponds to the production of cAMP induced by a concentration of 10 -8 M of GLP-1 and the value at 0% corresponds to the basal production in the absence of GLP-1.
  • EC 50 is the concentration which induces 50% of the production of cAMP obtained by a concentration of 10 -8 M of GLP-1.
  • the compounds of the invention have an agonist character. They increase the production of cAMP and have EC 50 nanomolar or subnanomolar values. As an example, the compound of Example 7 has an EC 50 of 1.02.10 -9 M.
  • the stimulation of insulin production induced by the compounds of the invention is studied on Min6 cells (5 ⁇ 10 5 cells per plate in 0.5 ml of culture medium). 18 hours before the experience. the culture medium is pipetted and the cells are washed twice with DRB pH 7.5 containing 0.1% BSA. The cells are then preincubated for one hour in DRB-BSA containing 1 mM of glucose and then incubated in DRB-BSA containing different concentrations of glucose and of test compound. After incubation, the medium is collected, centrifuged for 5 minutes and stored at -20 ° C. Insulin secretion is determined by radioimmunoassay using iodine-labeled porcine insulin 125 and guinea pig Kervran antiinsulin antibody.
  • the compounds of the invention are capable of stimulating the secretion of insulin to a greater extent than t GLP-1.
  • Each compound is dissolved in 50 mg / ml of BSA in a 1% aqueous solution of trifluoroacetic acid, so as to obtain a concentration of 1 mg / ml.
  • the results obtained with t GLP-1 and with the compound of Example 7 are grouped in the following table: Compound Incubation time Human plasma (% peptide remaining) DPP IV% remaining peptide Example 7 5 100 - 10 100 100 15 100 - 30 100 - 60 100 - t GLP-1 5 83 - 10 65 8 15 53 - 30 29 - 60 10 -
  • the antihyperglycemic activity of the derivatives of the invention was sought on normal male Wistar rats of approximately 250 g aged three months. Homeostasis was assessed by a glucose tolerance test.
  • IVGTT Intravenous glucose tolerance test
  • the glucose is dissolved in a 0.9% aqueous NaCl solution and administered by the saphenous vein to rats anesthetized with pentobarbital (60 mg.kg -1 , PI ).
  • Blood samples are collected sequentially by the tail vessels before and 2, 5, 10, 15, 20 and 30 minutes after the glucose injection. They are then centrifuged and the plasma is separated. The plasma glucose concentration is determined immediately on an aliquot of 10 ⁇ l and the remaining plasma is stored at -20 ° C, until the insulin concentration is determined by radioimmunoassay.
  • a single iv injection of the product to be tested is carried out in fasted rats anesthetized with pentobarbital immediately after the glucose loading according to the protocol described by Hendrick et al. (Metabolism, 1993, 42 , 1).
  • the plasma glucose concentration is determined using a glucose analyzer (Beckman Inc., Fullerton, CA). Glucose tolerance is measured in relation to two parameters: ⁇ G and K.
  • ⁇ G represents the increase in blood sugar above the baseline, integrated over a period of 30 minutes, after glucose overload at a dose of 1 g / kg.
  • K is the rate of disappearance of glucose between 5 and 30 minutes, after administration of the glucose.
  • the compounds of the invention have an insulin-secreting and antihyperglycemic activity equivalent to or greater than that of t GLP 1 , have a longer duration of action and greater metabolic stability in vivo.
  • Example 7 Composed of Example 7 10 mg Distilled water for injections 25 ml

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EP99400613A 1998-04-10 1999-03-12 Peptidanaloge des Glucagon-ähnlichen-Peptids-1 (7-37), deren Herstellung und pharmazeutische Zusammensetzungen Expired - Lifetime EP0955314B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9804559A FR2777283B1 (fr) 1998-04-10 1998-04-10 Nouveaux composes peptidiques analogues du glucagon-peptide- 1 (7-37), leur procede de preparation et les compositions pharmaceutiques qui les contiennent
FR9804559 1998-04-10

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EP0955314A2 true EP0955314A2 (de) 1999-11-10
EP0955314A3 EP0955314A3 (de) 2000-03-29
EP0955314B1 EP0955314B1 (de) 2003-12-03

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US (1) US6620910B1 (de)
EP (1) EP0955314B1 (de)
JP (1) JP3787242B2 (de)
CN (1) CN1305897C (de)
AT (1) ATE255596T1 (de)
AU (1) AU761652B2 (de)
BR (1) BR9902014A (de)
CA (1) CA2263059A1 (de)
DE (1) DE69913242T2 (de)
DK (1) DK0955314T3 (de)
ES (1) ES2212485T3 (de)
FR (1) FR2777283B1 (de)
HK (1) HK1022320A1 (de)
HU (1) HUP9900604A3 (de)
NO (1) NO323137B1 (de)
NZ (1) NZ334379A (de)
PL (1) PL331960A1 (de)
PT (1) PT955314E (de)
ZA (1) ZA992035B (de)

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WO2002022151A2 (en) * 2000-09-18 2002-03-21 Osteometer Bio Tech A/S Use of glp-1 and flp-2 peptides for treatment of bone disorders
EP1572892A2 (de) * 2001-10-18 2005-09-14 Bristol-Myers Squibb Company Menschliches glucagonähnliches peptid 1 imitierende substanzen und ihre verwendung bei der behandlung von diabetes und verwandten leiden
US7186683B2 (en) 2000-09-18 2007-03-06 Sanos Bioscience A/S Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7371721B2 (en) 2000-09-18 2008-05-13 Sanos Bioscience A/S Use of GLP-2 and related compounds for the treatment, prevention, diagnosis, and prognosis of bone-related disorders and calcium homeostasis related syndromes
EP2329839A1 (de) 2002-01-10 2011-06-08 Imperial Innovations Limited Änderung des Fütterverhaltens durch GLP-1 und PYY
EP2371378A1 (de) 2003-01-10 2011-10-05 Imperial Innovations Limited Veränderung des Fütterungsverhaltens und Gewichtskontrolle mit Oxyntomodulin
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour
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KR20050037004A (ko) * 1998-12-07 2005-04-20 소시에떼 더 콘세이유 더 레세르세 에 다플리까띠옹 시엔띠피끄, 에스.아.에스. Ｇｌｐ-1의 유사체
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US7332819B2 (en) * 2002-01-09 2008-02-19 Micron Technology, Inc. Stacked die in die BGA package
US8058233B2 (en) * 2002-01-10 2011-11-15 Oregon Health And Science University Modification of feeding behavior using PYY and GLP-1
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US8377869B2 (en) * 2007-10-24 2013-02-19 Mannkind Corporation Method of preventing adverse effects by GLP-1
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US7550590B2 (en) 2003-03-25 2009-06-23 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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JP2007505121A (ja) 2003-09-08 2007-03-08 武田薬品工業株式会社 ジペプチジルぺプチダーゼ阻害剤
JP2007536214A (ja) * 2003-12-16 2007-12-13 ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス Ｇｌｐ−１類似体
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US7732446B1 (en) 2004-03-11 2010-06-08 Takeda Pharmaceutical Company Limited Dipeptidyl peptidase inhibitors
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US7687638B2 (en) 2004-06-04 2010-03-30 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
WO2006019965A2 (en) 2004-07-16 2006-02-23 Takeda San Diego, Inc. Dipeptidyl peptidase inhibitors
ATE486064T1 (de) 2004-08-20 2010-11-15 Mannkind Corp Katalyse der diketopiperazinsynthese
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TW200643033A (en) * 2005-03-08 2006-12-16 Chugai Pharmaceutical Co Ltd Conjugate of water-soluble modified hyaluronic acid and glp-1 analogue
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DK1928423T3 (en) 2005-09-14 2016-02-29 Mannkind Corp A method for drug formulation based on increasing the affinity of the active substances to the crystalline microparticle surfaces
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GB0522295D0 (en) * 2005-11-01 2005-12-07 Activotec Spp Ltd Peptides and uses thereof
WO2007051987A1 (en) * 2005-11-01 2007-05-10 Activotec Spp Limited Insulinotropic compounds and uses thereof
EP1986679B1 (de) 2006-02-22 2017-10-25 MannKind Corporation Verfahren zur verbesserung der pharmazeutischen eigenschaften von mikropartikeln mit diketopiperazin und einem wirkstoff
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US7186683B2 (en) 2000-09-18 2007-03-06 Sanos Bioscience A/S Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders
US8217001B2 (en) 2001-09-24 2012-07-10 Imperial Innovations Limited Modification of feeding behavior
EP1572892A2 (de) * 2001-10-18 2005-09-14 Bristol-Myers Squibb Company Menschliches glucagonähnliches peptid 1 imitierende substanzen und ihre verwendung bei der behandlung von diabetes und verwandten leiden
EP1572892A4 (de) * 2001-10-18 2007-08-22 Bristol Myers Squibb Co Menschliches glucagonähnliches peptid 1 imitierende substanzen und ihre verwendung bei der behandlung von diabetes und verwandten leiden
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US7238670B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US7238671B2 (en) 2001-10-18 2007-07-03 Bristol-Myers Squibb Company Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
EP2329839A1 (de) 2002-01-10 2011-06-08 Imperial Innovations Limited Änderung des Fütterverhaltens durch GLP-1 und PYY
EP2371378A1 (de) 2003-01-10 2011-10-05 Imperial Innovations Limited Veränderung des Fütterungsverhaltens und Gewichtskontrolle mit Oxyntomodulin
US8101576B2 (en) 2006-12-13 2012-01-24 Imperial Innovations Limited Compounds and their effects on feeding behaviour

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PL331960A1 (en) 1999-10-11
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PT955314E (pt) 2004-03-31
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HU9900604D0 (en) 1999-05-28
HK1022320A1 (en) 2000-08-04
AU2368899A (en) 1999-10-21
FR2777283B1 (fr) 2000-11-24
HUP9900604A2 (hu) 1999-09-28
ATE255596T1 (de) 2003-12-15
CN1232038A (zh) 1999-10-20
ES2212485T3 (es) 2004-07-16
CN1305897C (zh) 2007-03-21
US6620910B1 (en) 2003-09-16
AU761652B2 (en) 2003-06-05
NO323137B1 (no) 2007-01-08
EP0955314B1 (de) 2003-12-03
NZ334379A (en) 1999-10-28
DE69913242T2 (de) 2004-09-09
ZA992035B (en) 1999-09-27
HUP9900604A3 (en) 2001-01-29
EP0955314A3 (de) 2000-03-29
DE69913242D1 (de) 2004-01-15
BR9902014A (pt) 2000-05-02
NO991199D0 (no) 1999-03-11
CA2263059A1 (fr) 1999-10-10
NO991199L (no) 1999-10-11
DK0955314T3 (da) 2004-04-13

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